Photoreceptor peripherin/rds belongs to a growing family of proteins known as tetraspanins. These proteins act as molecular facilitators and form large multi-functional complexes. Interest in peripherin/rds has increased with the recognition that a plethora of retinal degenerative diseases are linked to, and presumably caused by, mutations within this photoreceptor specific protein. A general feature of the disease phenotypes includes disruption of the normal length and structure of the photoreceptor ROS, most likely due to disruptions in the normal renewal processes of disk morphogenesis and disk shedding. These two essential processes in the ROS depend upon membrane fusion events. Our working hypothesis holds that through its function as a photoreceptor specific membrane fusion protein, peripherin/rds contributes differentially to the etiology of the various retinal degenerative diseases. This application seeks to establish an in vivo model of ROS fusion processes based on an understanding of the fusogenic function of peripherin/rds and expands previous work to include an analysis of the regulatory mechanisms governing fusion processes. The following Specific Aims provide the experimental strategy utilized to meet these goals: Aim # 1 will identify a gain of function and loss of function peripherin/rds varient using site-directed mutagenesis, recombination studies and biochemical analyses. Aim # 2 will critically evaluate the role of rom-1 and a newly identified protein inhibitor, dsu, in the regulation of fusion processes, using membrane raft isolation techniques, mutagenesis studies and membrane fusion assays. Aim # 3 will analyze reported pathogenic peripherin/rds mutations for their effect on membrane fusion using mutagenesis, in vivo recombination studies and biochemical assays. We will evaluate how retinitis pigmentosa and macular degeneration-linked mutations effect fusogenic function. Aim # 4 will establish an in vivo model of photoreceptor fusion using gain of function and loss of function peripherin/rds mutant transgene(s) on rds -/- and rds -/+ genetic backgrounds.